The aim of the research is to discover the underlying reactions responsible for the carcinogenicity of nitroso compounds and to ascertain whether there are protective mechanisms by which the cell can minimize the damage produced by these agents. The hypothesis that carcinogenesis is due to the formation and persistence in DNA of the promutagenic base, O6-methylguanine, is being studied. The reactions responsible for the formation of, and subsequent loss of this project are being studied in a number of different tissues known to differ in their susceptibility to the carcinogenic insult produced by the nitrosamines. At present, all of the data collected is consistent with the hypothesis and it appears that the relative resistance of the liver to carcinogenesis is due to the high efficiency with which this abnormal purine can be removed from liver DNA. The studies are being carried out using dimethylnitrosamine which produces liver and kidney tumors in rats, N-methyl-N-nitrosourea which produces tumors in the nervous system and in other organs and 1,2-dimethylhydrazine which gives rise to tumors in the colon. The enzyme responsible for the removal of O6-methylguanine from rat liver has been partially purified and the properties of this enzyme are currently under investigation.